Transmucosal Administration System for a Pharmaceutical Drug

ABSTRACT

The present invention relates to a transmucosal administration system to administer quinones, benzoquinones, and especially 1,4-benzoquinones, via the oromucosal route.

FIELD OF THE INVENTION

The present invention relates to a transmucosal administration system toadminister quinones, benzoquinones, and especially 1,4-benzoquinones viathe oromucosal route to a patient. Specifically, the present inventionrelates to a transmucosal administration system to administer2,3-dimethoxy-5-metriyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone)and its analogues via a film formulation (oral wafer).

BACKGROUND OF THE INVENTION

Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), a vital cellmembrane antioxidant and essential constituent of theadenosine-triphosphate (ATP) producing mitochondrial electron transportchain (ETC). Up to now, idebenone has been used in a variety of medicalapplications. Similar to coenzyme 010, idebenone undergoesreduction/oxidation cycles in living organisms and reduced idebenone isan antioxidant and radical scavenger (A. Mordente, G. E. Martorana, G.Minotti, B. Giardina, Chem. Res. Toxicol. 11 (1998), 54-63). It is knownthat idebenone protects cell membranes and mitochondria from oxidativedamage because of its ability to inhibit lipid peroxidation (M. Suno, M.Shibota, A. Nagaoka, Arch. Gerontol. Geriatr. 8 (1989). 307-311).Idebenone also interacts with the ETC, preserving ATP formation inischemic states. It has been shown that the compound stimulates nervegrowth factor, a characteristic that could be important for thetreatment of Alzheimer's and other neurodegenerative diseases (K.Yamada, A. Nitta. T. Hasegawa, K. Fuji, M. Hiramatsu, T. Kameyama, Y.Furukawa, K. Hayashi, T. Nabeshima, Behav. Brain Res. 83 (1997).117-122). The compound has also been suggested for the treatment ofFriedreich's Ataxia and other mitochondrial and neuromuscular diseases(A. O. Hausse, Y. Aggoun, D. Bonnet, D. Sidi, A. Munnich, A. Rotig, P.Rustin, Heart 87 (2002), 346-349; Di Prospero N. A., Baker A., JeffriesN. Fischbeck K. H. Lancet Neurol 6 (2007) 878-886).

As a lipophilic compound idebenone is well absorbed in thegastrointestinal tract after conventional oral administration, which isthe normal route for administering said compound. Dosage forms such astablets or capsules have been used in clinical trials and as marketedproduct. In the course of our investigations on the pharmacologicalprofile of idebenone, we discovered that the compound, after beingabsorbed in the gut, is metabolized very quickly during its firstpassage through the liver (“first-pass-effect”). Experiments showed thatmore than 98% of the idebenone is metabolized during its first passagethrough the liver. Hepatic metabolism of idebenone results in side chainoxidation, reduction of the quinone ring, sulphate and glucuronideconjugation and subsequent renal excretion. The high liver metabolismgreatly reduces the potentially high plasma levels of thepharmacologically active idebenone. Because of this strong first passmetabolism, oral administration of idebenone requires high doses of thecompound to achieve pharmacologically efficacious plasma levels in thebody. Said high doses can result in unwanted side effects such asdiarrhea.

In addition, the requirement for oral formulations of idebenone to beswallowed inflicts difficulties in the practical administration topatients with swallowing problems, e.g. a patient with a seriousneuromuscular disease such as Duchenne Muscular Dystrophy orFriedreich's Ataxia, elderly or young patients.

SUMMARY OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION

A solution to this problem is presented in this invention which is basedon data obtained with a specific type of transmucosal administrationsystem consisting of especially a thin polymer-based film that whenattached to the oral mucosa releases the active ingredient directly tothe mucosa or partly into the saliva in the oral cavity, esophagus andstomach.

The active ingredient is absorbed through the mucosa primarily in theoral cavity, esophagus and stomach, thus avoiding the first-passmetabolism observed after conventional oral administration andgastrointestinal absorption. This dosage form is also described as oralwafer.

The principle of this system is also applicable to analogues ofidebenone, such as other benzoquinones or quinones, having a reversiblyreducible quinone ring, with a lipophilic side chain. The term“ubiquinone analogues”, as used herein, encompasses natural ubiquinones(coenzyme Q-n) as well as their structural analogs having a reversiblyreducible quinone ring with a lipophilic side chain, for exampleidebenone or decylubiquinone.

Said object has been achieved by the use of a preferably thin filmformulation (oral wafer) containing especially idebenone. Surprisinglyit has been shown (see FIGURE) that the plasma levels of idebenone afteroromucosal administration of wafer A (containing 30 mg), wafer B(containing 15 mg as a solid solution) are significantly higher comparedto oral administration (300 mg/kg as microemulsion) in the same Beagledogs (n=3).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical illustration of the mean plasma concentrationsversus time of free idebenone after single administrations of variousexemplary formulations (oral and thin wafer) in female Beagle dogs.

DETAILED DESCRIPTION OF ADVANTAGEOUS EMBODIMENTS OF THE INVENTION

The present invention relates to a transmucosal formulation, whichcomprises an effective amount of an active ingredient of the generalstructural formula (I) wherein R¹ is a lower alkyl group; R² is ahydrogen atom or an alkyl or alkenyl group which may be substituted; R³and R⁴ each independently means a lower alkyl or lower alkoxy group or,taken together, mean a butadienylene group.

Referring to the above general formula (I), the lower alkyl group R¹ isa lower alkyl group of 1 to 4 carbon atoms, such as methyl, ethyl,propyl, butyl and so on. The alkyl moiety of the unsubstituted orsubstituted alkyl group R² includes acyclic hydrocarbon residues of 1 to22 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, pentadecyl,heptadecyl, eicosyl, docosyl and so on. Among them, an alkyl having 8 to13 carbon atoms is preferable.

The alkenyl moiety of the unsubstituted or substituted alkenyl group R²include acyclic hydrocarbon residues of 2 to 15 carbon atoms, such asethenyl, 1-propenyl, 3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl,etc., wherein the number of double bonds may generally range from 1 to 3and these double bonds may be conjugated. Examples of substituents onthe alkyl and alkenyl groups R² include hydroxy, carboxy, alkoxycarbonyl(e.g. C1-4 alkoxycarbonyl groups such as methoxycarbonyl,ethoxycarbonyl, propionyloxycarbonyl, butoxycarbonyl, etc.), aryl (e.g.phenyl, 1-naphthyl, 2-naphthyl, indanyl, etc.), heterocyclic groups(e.g. 2-pyridyl, 3-pyridyl, 2-thienyl, 3-thienyl, etc.) and halogen(e.g. fluorine, chlorine, bromine and iodine). Where the substituentgroup is such an aryl group or a heterocyclic group, the group may benuclearly substituted by one or more substituents in optional positionsof the ring structure. The substituents mentioned just above include,but are not limited to, unsubstituted C1-4 alkyl groups (e.g. methyl,ethyl, propyl, butyl, etc.), hydroxy, carboxy, and C2-5 alkoxycarbonyl(e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,etc.). The position of substitution on the alkyl or alkenyl group R² isoptional but preferably 1-position or .omega.-position. The lower alkylgroup, represented by R³ and R⁴, may be a C1-6 alkyl group, such asmethyl, ethyl, propyl, i-propyl, butyl, i-butyl, sec-butyl, t-butyl,amyl, hexyl, etc. and preferably a C1-3 alkyl group. These lower alkylgroups may have substituents such as hydroxy, halogen (fluorine,chlorine, bromine and iodine), nitro, trifluoromethyl, carboxy, C2-5alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, etc.), 3-pyridyl,1-imidazolyl, 5-thiazolyl and so on. The lower alkoxy group, representedby R³ and R⁴, may be a C1-3 alkoxy group such as methoxy, ethoxy,propoxy, i-propoxy and so on. Where R³ and R⁴ mean a butadienylenegroup, they constitute a benzene ring in association with the carbonatoms to which R³ and R⁴ are respectively attached, and the benzene ringso constituted may have 1 to 3 substituent groups in optional positions,which substituent groups include, among others, lower (C1-3) alkylgroups (e.g. methyl, ethyl, propyl, etc.), lower (C1-3) alkoxy groups(e.g. methoxy, ethoxy, propoxy, etc.), hydroxy, nitro and halogen.

The present invention relates also to the use of quinone orbenzoquinone, especially idebenone (International Nonproprietary Name(INN): idebenone; Chemical name:2-(10-Hydroxydecyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadiene-1,4-dione;Chemical Abstracts Service (CAS) registry number: 58186-27-9) and itsanalogues for the preparation of a preferably thin film formulation thatwhen attached to the oral mucosa releases the active ingredient directlyto the mucosa or partly into the saliva in the oral cavity (also calledoral wafer) and is used for transmucosal administration to human beingsor animals. This type of system results in much higher plasma levels ofthe compound compared to the oral route of administration. The preferredtransmucosal administration system for a pharmaceutical activeingredient as thin film (oral wafer) formulations comprising as anactive ingredient idebenone together with additives and excipients inconjunction with an appropriate manufacturing process used for this typeof formulations are further described herein.

Idebenone has the following chemical structural formula (II):

2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone, idebenoneIdebenone, a member of the quinone family, has been promotedcommercially as a synthetic analog of Coenzyme Q10, and has beenindicated to be suitable for treating a number of diseases and/orconditions. Moreover, it has been made the subject of various medicalstudies investigating its efficacy in the treatment of, for example,neuromuscular diseases such as Friedreich's Ataxia or neurologicaldiseases such as Alzheimer's disease. Idebenone has also been used intopical applications to treat wrinkles. Therefore, idebenone may beregarded as toxicologically safe which means that it can be used as apharmaceutical active agent in a medication. The toxicological safety ofIdebenone has been confirmed in a clinical study with 536 patients thathave been treated with up to 360 mg of idebenone t.i.d. (ter in die).Compared to the placebo treated control group, no treatment emergentadverse events except some gastrointestinal irritations as well as aslight increase in orthopedic events were observed (L. J. ThaI, M.Grundman, J. Berg, K. Emstrom, R. Margolin, E. Pfeiffer, M. F. Weiner,E. Zamrini. R. G. Thomas, Neurology 61 (2003), 1498-1502).

It has now been observed that, after conventional oral administrationand absorption in the gut, idebenone is rapidly metabolized during itsfirst passage through the liver. The major metabolites are idebenoneconjugates such as glucuronates and sulphates as well as derivativeswhere the side chain of the parent compound has been oxidized. Themetabolites of idebenone are pharmacologically not significantly activeand they are rapidly excreted. Due to this strong first pass metabolism,oral administration of idebenone requires high doses in order to reachpharmacologically active plasma levels. These high doses result inunwanted effects such as diarrhea and gastrointestinal (GI) tractdisturbances which are frequently observed in clinical applications.

Using the preferred thin film formulation (oral wafer) it hassurprisingly been found that even with a 20-fold lower dose compared tothe oral administration route, a more than 5-fold AUC can be achievedwhich, on a dose-normalized level, leads to a >100-fold AUC (see Table4). Moreover, this opens up possibilities to achieve plasma levels ofthe pharmacologically active molecule that are far above thoseachievable via the oral route of administration.

By use of this system and the transmucosal route of administration, thehigh first pass metabolism observed after conventional oraladministration of idebenone can very effectively be circumvented.

Circumvention of the strong first-pass metabolism of idebenone by usingthe thin film formulation (oral wafer) enables;

-   -   a) similarly high plasma levels of this active ingredient to be        obtained whilst significantly reducing the dose that has to be        administered. Lower active ingredient exposure is generally        believed to be associated with a reduced risk of adverse side        effects and offers a medical advantage leading to improved        compliance by the patient. In the particular case of idebenone,        the described GI side effects that can be avoided.    -   b) significantly higher plasma levels compared to those        achievable with an oral formulation of the active ingredient        being absorbed via the gastrointestinal route. This may lead to        extension of the use of idebenone to additional, new indications        in the field of neuromuscular diseases that require high        concentrations e.g. in order to cross the blood-brain-barrier.    -   c) increased patient convenience as the film formulation (oral        wafer) is thin, easy to handle and one unit is able to replace        swallowing of several large tablets.    -   d) administration of a thin film formulation (oral wafer) to        patients with swallowing difficulties, such as patients        suffering from certain neuromuscular diseases or children below        the age of 8, could increase compliance and convenience of use.

In the present invention, “thin film formulations” or “oral wafer” meansa formulation that is intended to be applied and/or administered to theoral mucosa of a patient and where the active ingredient is absorbedinto the body through the mucosa. According to the invention, suchformulation constitutes the basis of medication containing idebenone forthis specific route of administration. The oral mucosa comprise themucosa in the entire oral and connecting cavities including but notlimited to the sublingual, buccal, gingival, lingual, as well as theesophageal mucosa. The system has preferably a monolayer or double-layerconstruction.

The objective upon which the present invention is based is achievedthrough an transmucosal administration system which dissolves in themouth of a patient and which comprises 0.01 to 80% by weight, preferably2-70% by weight, of at least one quinone and 20-99.99% by weight,preferably 30-98% by weight, of a carrier material. Suitable carriermaterials are in particular cellulose and derivatives thereof, such asmethylcellulose, ethylcellulose, hydroxypropyl-cellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose (HPMC),carboxymethylcellulose (CMC); poly-alcohols such as poly-vinyl-alcohol(PVA); poly-N-vinylpyrrolidones; vinyl-pyrrolidone-vinyl acetatecopolymers; starch; starch derivatives; gelatin; gelatin derivatives;Soluplus (a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft copolymer); Kollicoat, (a polyvinyl alcohol-polyethylene glycolgraft copolymer) and combinations thereof. The administration systemreleases the quinone contained therein with a high bioavailability.Preferably, the system will be able to achieve high bioavailabilitywithout the addition of permeation enhancers.

An administration system containing a suspension of the activeingredient would preferably comprise 30-60% by weight, particularlypreferably 40-50% by weight, of a quinone—especially of an1,4-benzoquinone—and 40-70% by weight, preferably 50-60% by weight of acarrier material—especially a poly-alcohol and/or a cellulose derivativewherein the active ingredient is preferably micronized. Micronisationinvolves the reduction of particles to a size of preferably less than100 μm, particularly preferably less than 10 μm.

An administration system containing an amorphous presentation (oramorphous composition) of the active ingredient would preferablycomprise 3-20% by weight, particularly preferably 5-10% by weight of aquinone—especially of a 1,4-benzoquinone—and 80-97% by weight,preferably 90-95% by weight of a carrier material—especially a suitablysubstituted carbohydrate or other water soluble polymer.

An administration system containing an emulsion of the active ingredientwould preferably comprise 3-50% by weight, particularly preferably 5-30%by weight of a quinone—especially of a 1,4-benzoquinone—and 50-97% byweight, preferably 79-95% by weight of a carrier material—especially acellulose derivative.

One particularly preferred administration system comprises 50% by weightof a 1,4-benzoquinone of the group consisting of idebenone, idebenoneanalogues, ubiquinone, or ubiquinone analogues and 40% by weight ofpoly-vinyl alcohol (PVA) and 10% by weight of sodiumcarboxymethyl-cellulose carrier material.

Another particularly preferred administration system comprises 10% byweight of a 1,4-benzoquinone of the group consisting of idebenone,idebenone analogues, ubiquinone, or ubiquinone analogues and 90% byweight of HPMC carrier material.

It is preferred for the present invention that the administrationsystems which dissolves in the mouth to be in film form. Theseadministration systems in film form are also referred to as “strips” or“wafers”. The inventive administration systems in film form can, in aparticular embodiment, be designed such that it has mucoadhesion. Bythis, it is meant that the property of adhering to a mucous membrane ofa patient, specifically in such a manner that it is difficult orimpossible to detach the administration system from the mucous membranesubsequent to the application.

For the present invention, it is preferred that the film administrationsystem have a high surface area to weight ratio. It is also preferredthat the administration system is in or forms a gel-like consistency inthe oral cavity upon swelling in saliva.

The administration systems in film form of the present invention have anarea of between 1 and 10 cm², preferably between 2 and 8 cm² andparticularly preferably between 5 and 7 cm². They, moreover, have aweight per unit area between 50 and 250 g/m², preferably between 100 and150 g/m². The latter approximately correlates with a thickness ofbetween 40 and 300 μm, preferably between 50 and 100 μm.

The administration system dissolves in the mouth of a patient preferablyin a period of less than 30 min, particularly preferably in a period ofless than 15 min. The quinone which enters the bloodstreamtransmucosally from the administration system leads to a rapid rise inthe concentration of this quinone in the blood. In this case, a maximumconcentration of the quinone in the blood is reached preferably in aperiod of less than 60 min—particularly preferably in a period ofbetween 5 and 30 min—after application. It is possible with theadministration system to achieve a relatively high bioavailability, asmeasured by the AUC of the active ingredient concentration in the blood,of at least a factor of 5 times (500%) greater, preferably of at least afactor of 10 (1000%) greater than that of the quinone in tablet form (orsimulated tablet form), when adjusted for the dose administered. Aparticularly preferred increase in bioavailability would be a factor of20 (2000%) greater.

The administration system in film form may, besides the carrier materialand the quinone, comprise further substances, for example flavorings,colorants, sweeteners, fillers, plasticizers, surface-active substances,liquid—preferably lipophilic—excipients which are able to dissolve thequinone and form a second phase in the—preferably hydrophilic—carriermaterial, solubilizers, pH stabilizers, disintegrants, solubilityenhancers, absorption enhancers, and or permeation enhancers.

Quinones according to the present invention may be 1,4-hydroquinones andrelated compounds. The preferred 1,4-hydroquinones are idebenone,idebenone analogues, and ubiquinone and their related compounds. Theterm “ubiquinone and their related compounds”, as used herein,encompasses natural ubiquinones (coenzyme Q-n) as well as theirstructural analogs having a reversibly reducible quinone ring with alipophilic side chain.

The transmucosal administration system of 1,4-hydroquinones and relatedcompounds according to the present invention can be used in thetreatment of patients suffereing from various diseases and/orconditions, including mitochondrial, neuromuscular or neurologicaldiseases. Examples of diseases to be treated include, but are notlimited to, Friedreich's Ataxia, Duchenne Muscular Dystrophy. BeckerMuscular Dystrophy. Alzheimer's Disease, Leber's Hereditary OpticNeuropathy, MELAS (mitochondrial myopathy, encephalopathy, lacticacidosis with stroke-like episodes), Parkinson's Disease andmitochondrial myopathies. In addition, there is preliminary evidencethat the 1,4-benzoquinone, Coenzym Q10 or CoQ10, may be effective intreating coronary heart disease, Myoclonic epilepsy and ragged-redfibers, Kearns-Sayre syndrome, progressive external ophthalmoplegia,Diabetes mellitus and deafness, Leigh syndrome, subacute sclerosingencephalopathy, NARP (Neuropathy, ataxia, retinitis pigmentosa, andptosis), and Myoneurogenic gastrointestinal encephalopathy, migraines,cancer, hypertension, age-related macular degeneration, Alzheimer'sdisease, Anthracycline chemotherapy heart toxicity, asthma and manyothers. Another particular application is the co-administration of1,4-benzoquinone with statins and beta blockers to patients.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment of amitochondrial disease, preferably selected from the group consisting ofLeber's hereditary optic neuropathy (LHON), autosomal dominant opticatrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract,optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy,lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy withragged red fibers (MERRF), myoneurogenic gastrointestinalencephalomyopathy (MNGIE). Keams-Sayre syndrome, CoQ10 deficiency, andmitochondrial complex deficiencies (1-5, CPEO);

a neurodegenerative disease, preferably selected from the groupconsisting of Friedreich's ataxia (FRDA), amyotrophic lateral sclerosis(ALS), Parkinson's disease, Alzheimer's disease. Huntington's disease,stroke/reperfusion injury, and dementia;a neuromuscular disease, preferably selected from the group consistingof Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD),Limb-Girdle muscular dystrophy (LGMD), X-linked dilated cardiomyopathy(XLDCM), Pantothenate kinase-associated neurodegeneration (PKAN), spinalmuscular atrophy (SMA), multiple sclerosis, relapsing remitting multiplesclerosis (RR-MS), primary progressive multiple sclerosis (PP-MS),secondary progressive multiple sclerose (SP-MS). Kugelberg-Welanderdisease, and Werdnig-Hoffmann disease;a psychiatric disorder, preferably selected from the group consisting ofschizophrenia, major depressive disorder, bipolar disorder, andepilepsy;a metabolic disorder, preferably selected from the group consisting ofageing-related physical decline, obesity, overweight, type II diabetes,and metabolic syndrome:cancer: multiple sclerosis; orimmune dysfunction, preferably selected from the group consisting ofarthritis, psoriasis and rheumatoid arthritis.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment of amitochondrial disease. Preferably, the mitochondrial disease is selectedfrom the group consisting of Leber's hereditary optic neuropathy (LHON),autosomal dominant optic atrophy (DOA), macular degeneration, glaucoma,retinopathy, cataract, optic disc drusen (ODD), mitochondrial myopathy,encephalomyopathy, lactic acidosis, stroke-like symptoms (MELAS),myoclonic epilepsy with ragged red fibers (MERRF), myoneurogenicgastrointestinal encephalomyopathy (MNGIE), Kearns-Sayre syndrome. CoQ10deficiency, and mitochondrial complex deficiencies (1-5, CPEO).

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofLeber's hereditary optic neuropathy (LHON).

In a preferred embodiment in combination with any of the above or belowembodiments, the thin film drug delivery system is for use in thetreatment of mitochondrial myopathy, encephalomyopathy, lactic acidosis,stroke-like symptoms (MELAS).

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment of aneurodegenerative disease. Preferably, the neurodegenerative disease isselected from the group consisting of Friedreich's ataxia (FRDA),amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer'sdisease, Huntington's disease, stroke/reperfusion injury, and dementia.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment of aneuromuscular disease. Preferably, the neuromuscular disease is selectedfrom the group consisting of Duchenne muscular dystrophy (DMD), Beckermuscular dystrophy (BMD), Limb-Girdle muscular dystrophy (LGMD),X-linked dilated cardiomyopathy (XLDCM), Pantothenate kinase-associatedneurodegeneration (PKAN), spinal muscular atrophy (SMA), multiplesclerosis and primary progressive multiple sclerosis (PP-MS),Kugelberg-Welander disease, and Werdnig-Hoffmann disease.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofDuchenne muscular dystrophy (DMD).

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofprimary progressive multiple sclerosis (PP-MS).

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment of apsychiatric disorder. Preferably, the psychiatric disorder is selectedfrom the group consisting of schizophrenia, major depressive disorder,bipolar disorder, and epilepsy.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment of ametabolic disorder. Preferably, the metabolic disorder is selected fromthe group consisting of ageing-related physical decline, obesity,overweight, type II diabetes, and metabolic syndrome.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofcancer.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofmultiple sclerosis.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofprimary progressive multiple sclerosis, relapsing remitting multiplesclerosis and secondary progressive multiple sclerosis, more preferablyfor use in the treatment of primary progressive multiple sclerosis.

In a preferred embodiment in combination with any of the above or belowembodiments, the administration system is for use in the treatment ofimmune dysfunction. Preferably, the immune dysfunction is selected fromthe group consisting of arthritis, psoriasis and rheumatoid arthritis.

Compared to the efficacious dose of idebenone administered via theconventional oral route of administration and absorption in thegastrointestinal tract the efficacious dose of the formulation describedin this application is expected to be significantly lower. On the otherhand, it is expected that with this formulation and depending on theactual dose applied, significantly higher plasma levels and potentiallyincreased clinical efficacy may be achievable within patients. Moreover,due to the higher plasma levels the use of idebenone can be extended toadditional indications in the field of neuromuscular diseases thatrequire high concentrations of drug substance e.g. in order to cross theblood-brain-barrier within patients.

Suitable doses of the active ingredient administered by thin filmformulation (oral wafer) are 0.01 mg/kg/day to 60 mg/kg/day. Preferably,for example idebenone is administered in a dosage of 0.01 mg/kg/day to20 mg/kg/day, more preferably in a dosage of 0.01 mg/kg/day to 10mg/kg/day and even more preferably in a dosage of 0.01 mg/kg/day to lessthan 5 mg/kg/day. Most preferably, the dosage of the active ingredientidebenone is between 0.1 mg/kg/day to 4 mg/kg/day. Studies have shownthat, surprisingly, such low dosages achieve the required plasma levelof idebenone if it is applied via the oral mucosa. The required dosagemay be ascertained readily by a person skilled in the art.

In a preferred embodiment, idebenone may be administered in combinationwith a second therapeutic agent, wherein said second therapeutic agentis preferably selected from glucocorticosteroids such as6a-methylprednisolone-21 sodium succinate (SOLUMEDROL®) or deflazacort(CALCORT®) which are routinely used in DMD patients for treatment ofinflammation and muscle weakness. Likewise, idebenone may beadministered in combination with any medicament used in DMD patients totreat DMD-associated cardiomyopathy such as ACE-inhibitors,beta-blockers and diuretics as well as HMG-CoA reductase inhibitors.

In a further preferred embodiment, idebenone may be administered incombination with further therapeutic agents, wherein said furthertherapeutic agents are preferably erythropoietin, vitamin E, vitamin C,or mitoquinone (MitoQ; K. M. Taylor, R. Smith, WO05019232A1).

Idebenone and other therapeutic agents can be used simultaneously,separately or sequentially in order to treat or prevent the diseasesymptoms. The therapeutic agents may be provided in a single dosage formor as separate formulations, each formulation containing at least one ofthe active agents.

The following examples illustrate the invention, but are not intended tolimit the scope of the invention.

Example 1

112 g of PVA is added to 720 mL of water and stirred until dissolutionis complete. The dissolution is assisted where appropriate byapplication of heat. After cooling, 140 g of idebenone is disperseduniformly. Afterward. 28 g of CMC is added, and the mixture is stirreduntil dissolution is complete.

The mixture is degassed, coated and dried. A thin opaque film which isbetween 50 and 150 μm thick is produced. Opaque wafers with a content of30 mg of idebenone are obtained by cutting out samples of theappropriate size.

Example 2

28 g of idebenone are added to 720 mL of 75:25 methanol:water, which isstirred until the active ingredient has completely dissolved. 250 g ofHPMC are added and stirred until dissolution is complete. Degassing ofthe mixture and coating are followed by drying. A thin translucent filmwhich is between 100 and 300 μm thick is produced. Translucent waferswith a content of 15 mg of idebenone are obtained by cutting out samplesof the appropriate size.

It may be noted that the dried systems of example 1 comprise thebenzoquinone as particles in a separate phase suspended in the carriermaterial, whereas the benzoquinone in examples 2 is in the form of amono-molecular dispersion in the carrier material.

Experimental Data:

Pharmacokinetic Data after Oromucosal Delivery of Idebenone

Plasma levels of idebenone were studied after the administration of twodifferent thin film formulations (oral wafers) administered via theoromucosal route and compared to the profile obtained when idebenone isdosed by the oral route (gavage) in a micro-emulsion. The doses used inthis study were 30 mg oromucosal (oral wafer A, suspension type), 15 mgoromucosal (oral wafer B, solid solution type) and 300 mg oral(TPGS/Miglyol microemulsion administered by oral gavage). The study wasa three way cross-over study with one week wash-out betweenadministrations. Formulations were administered to female Beagle dogsunder fasted conditions. The pharmacokinetic exposure of free(unconjugated) idebenone and its total metabolites (total idebenone,total QS10, total QS6, and total QS4) was determined for eachformulation.

Blood samples were collected at several time points over 6 hours afteradministration. Concentrations of idebenone in plasma were measured byHPLC-MS/MS and pharmacokinetic parameters were calculated.

For this, idebenone was separated and quantified by HPLC-MS/MS: ForHPLC, a SYNERGI™ 4μ MAX-RP (50×2 mm) column (Phenomenex. Schlieren,Switzerland) was used. Column temperature: 50° C. Mobile phase A:water+30 mM NH₄OAc; mobile phase B: MeOH/H₂O 100/3 (v/v)+30 mM NH₄OAc,gradient elution (table 4). Flow: 250 μl/min and 400 μl/min.

Once separated, idebenone was quantified by ESI-MS/MS (API 4000,Perkin-Elmer-Europe BV, Rotkreuz, Switzerland) in positive mode.

TABLE 1 Pump-gradient program and time events for separation andquantification of idebenone Time mobile phase Flow [min] B [%] [μl/min]Comments 0.01 50 250 start gradient, HPLC eluent to MS 3.00 — 250 — 3.01— 400 — 3.75 95 400 end gradient 4.50 95 400 — 4.51 50 400 — 5.90 50 400— 5.91 50 250 — 29.99 50 250 pump shutdown 30.00 95 20

From times 0.01 to 3.75 min a linear gradient was used.

Idebenone conjugates such as glucuronates and sulphates have beenquantified after acidic hydrolysis as described by R. Artuch, C. Colomé,M. A. Vilaseca, A. Aracil. M. Pineda. J. Neurosci. Meth. 115 (2002),63-66.

The pharmacokinetic analysis included maximum plasma concentration(C_(max)), the time when maximum plasma concentration was observed(T_(max)), and the area under the plasma concentrations versus timecurve from time 0 h to 360 min (AUC_(0-360min)). The relativebioavailability of idebenone after sublingual administration compared tothe oral administration was calculated for each dog from normalized (1mg/kg) AUC values. The AUC ratios of the metabolites were alsocalculated. In addition, C_(max) a ratios, normalized to a 1 mg/kg dose,were calculated.

The results obtained are shown in Table 2 to below.

TABLE 2 Mean pharmacokinetic parameters of idebenone after oromucosal(30 mg wafer A) and (15 mg wafer B) vs. oral (300 mg, microemulsion)administration in dogs. C_(max) T_(max) AUC₀₋₃₆₀ Dosing [ng/ml] [min][min*ng/ml] 30 mg wafer A 248 15 6152 (micronized suspension) 15 mgwafer B 404 25 13864 (solid solution) 300 mg oral gavage 111 7 2305(microemulsion)

As shown in Table 2, the two wafer formulations of idebenoneadministered via the oromucosal route, prepared according to example 1and 2, clearly lead to significantly higher plasma levels of idebenonecompared to conventional oral administration. Both C_(max) and AUC₀₋₃₆₀were superior to the oral administration in both thin film (oral wafer)formulations. There is also a marked difference between wafer A, whichcontains 30 mg idebenone as micronized powder suspended in the polymermatrix, and wafer B, which contains only 15 mg but in a solid solution,i.e. molecularly dispersed state. The latter clearly dissolves much moreefficiently and is better absorbed.

FIG. 1 illustrates the mean plasma concentrations versus time of freeidebenone after single administrations of various formulations (oral andthin wafer) in female Beagle dogs.

As shown in FIG. 1, wafer B (15 mg, solid solution type wafer) showedthe highest C_(max) and the largest AUC compared to the other treatmentarms. Wafer A (30 mg, suspension type wafer) shows a higher C_(max) anda larger AUC compared to the oral route (300 mg, microsuspension).

TABLE 3 Mean pharmacokinetic parameters of idebenone after oromucosal(30 mg wafer A) and (15 mg wafer B) vs. oral (300 mg. microemulsion)administration in dogs after dose normalization per mg. C_(max)/mgAUC₀₋₃₆₀/mg Dosing [ng/ml] [min*ng/ml] 30 mg wafer A 8.3 205 (micronizedsuspension) 15 mg wafer B 26.9 924 (solid solution) 300 mg oral gavage0.4 7.7 (microemulsion)

As shown in Table 3: above, the magnitude of increase in exposureobtained with the two wafer formulations of idebenone administered viathe oromucosal route (prepared according to example 1 and 2) compared tothe oral route of administration becomes even more apparent afternormalization for differences in dose.

TABLE 4 Comparison of the mean pharmacokinetic parameters of thedifferent formulations after dose normalization per mg. C_(max)/mgAUC₀₋₃₆₀/mg Dosing [ng/ml] [min*ng/ml] Comparison 33 26 wafer A vs. oralgavage Comparison 144 121 wafer B vs. oral gavage Comparison 3.62 4.75wafer B vs. wafer A

As shown in Table 4: The comparison on a dose-normalized basis showsthat wafer A lead to a 26-fold higher AUC (33-fold C_(max)) than theoral formulation on a dose normalized level and wafer B lead to a121-fold higher AUC (144-fold C_(max)) in comparison to the oral route.The solid solution wafer B leads to >4-fold higher exposure of idebenonecompared to the suspension type wafer A.

In summary it can be concluded that

-   -   Oral-mucosal administration of idebenone by a thin film        formulation (oral wafer) based on the solid-solution technology        strongly improves the relative bioavailability of idebenone by        approximately 100 fold over oral administration. The main reason        for the increased bioavailability is the initial bypass of the        enterohepatic circulation.    -   On top of that, there is evidence that the absorption of        idebenone from this wafer is increased compared to an oral        administration of idebenone by gavage.    -   A wafer, based on the micronized suspension technology, also        improves the relative bioavailability of idebenone, though to a        lesser extent    -   The metabolic spectrum of idebenone is comparable after oral        administration by gavage and the oral-mucosal application        -   The oral wafer formulation offers the following advantages            over the formulations administered via the oral route:            -   Significant dose reduction (less side effects)            -   Higher plasma levels achievable            -   Increased patient convenience            -   Administration to patients with swallowing difficulties    -   The inventive systems may further comprise a polymer matrix and        the pharmaceutical active ingredient may be incorporated within        the polymer matrix as a suspension, a suspension after        micronization, an emulsion, a micro- or nano-emulsion, or in        solubilised and/or molecularly dispersed form.

1.-21. (canceled)
 22. A transmuccosal administration system for apharmaceutical active ingredient wherein the system contains asuspension comprising 30-60% by weight of an active ingredient of thestructural formula (I)

wherein R¹ is a C1-4 lower alkyl group; R² is a hydrogen atom or anoptional substituted alkyl or an optional substituted alkenyl group; R³and R⁴ each represents an optional substituted C1-6 lower alkyl or C1-3lower alkoxy group or, R³ and R⁴ taken together a butadienylene groupand 40-70% by weight of a carrier material comprising polyalcohol and/ora cellulose derivative and wherein the system is a mucoadhesive filmwhich dissolves in the mouth.
 23. The administration system as claimedin claim 22, wherein R¹ is a C1-4 lower alkyl group, R² is linear orbranched, saturated or unsaturated, aliphatic hydrocarbon orhydroxyalkyl chain from 5 to 50 carbon atoms and R³ and R⁴ is a C1-4alkyl group or a C1-3 alkoxy group.
 24. The administration system asclaimed in claim 22, wherein R¹ is a C1-4 alkyl; R2 is (a) hydrogen. (b)a C1-22 alkyl which is optionally substituted by 1 to 10 substituentsselected from the group consisting of (i) C1-4 alkyl, (ii) hydroxy.(iii) oxo, (iv) amino, (v) mono-C1-6 alkylamino, (vi) di-C1-6alkylamino, (vii) carboxy. (viii) C1-4 alkoxy-carbonyl, (ix) C6-14 arylwhich is optionally substituted by 1 or 2 substituents selected from thegroup consisting of C1-4, alkyl, hydroxy, carboxy and C1-6alkoxy-carbonyl, (x) 5 or 6-membered heterocyclic group which isoptionally substituted by 1 or 2 substituents selected from the groupconsisting of C1-4 alkyl, hydroxy, carboxy and C1-6 alkoxy-carbonyl, and(xi) halogen, or (c) a C2-15 alkenyl which is optionally substituted by1 to 10 substituents selected from the group consisting of (i) C1-4alkyl, (ii) hydroxy, (iii) oxo, (iv) amino, (v) mono-C1-6 alkylamino,(vi) di-C1-6 alkylamino, (vii) carboxy. (viii) C1-4 alkoxy-carbonyl,(ix) C6-14 aryl which is optionally substituted by 1 or 2 substituentsselected from the group consisting of C1-4 alkyl, hydroxy, carboxy andC1-6 alkoxy-carbonyl, (x) 5- or 6 membered heterocyclic group which isoptionally substituted by 1 or 2 substituents selected from the groupconsisting of C1-4 alkyl, hydroxy, carboxy and C1-6 alkoxy-carbonyl, and(xi) halogen: R³ and R⁴ each is a C1-6 alkyl which is optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhydroxy, halogen, nitro, C1-3 alkyl which is optionally substituted withhalogenated, carboxy, C1-6 alkoxy-carbonyl, 3-pyridyl, 1-imidazolyl and5-thiazolyl or a C1-3 alkoxy; or R³ and R⁴ form, taken together with therespective adjacent carbon atoms, a benzene ring which is optionallysubstituted by 1 to 3 substituents selected from the group consisting ofC1-3 alkyl, C1-3 alkoxy, hydroxy, nitro and halogen.
 25. Theadministration system as claimed in claim 22, wherein R¹ is a C1-3alkyl, R2 is a C6-14 alkyl optionally substituted by hydroxy and R3 andR4 each is C1-3 alkoxy.
 26. The administration system as claimed inclaim 22, wherein said active ingredient is selected from the groupconsisting of idebenone, decylubiquinone, and ubiquinone.
 27. Theadministration system as claimed in claim 22, wherein the carriermaterial comprises cellulose, cellulose derivatives, polyvinyl-alcohol,poly-N-vinylpyrrolidones, vinylpyrrolidone-vinyl acetate copolymers,starch, starch derivatives, gelatine, gelatine derivatives, andcombinations thereof.
 28. The administration system as claimed in claim22, wherein the cellulose derivative is methylcellulose, ethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose or combinationsthereof.
 29. The administration system as claimed in claim 22, whereinsaid system comprises 50% by weight of a 1,4-benzoquinone as activeingredient selected from the group consisting of idebenone, orubiquinone and 40% by weight polyvinyl alcohol and 10% by weight ofsodium carboxymethyl-cellulose as carrier material, or said systemcomprises 10% by weight of a 1,4-benzoquinone as active ingredientselected from the group consisting of idebenone, or ubiquinone and 90%by weight of hydroxypropylmethylcellulose as carrier material.
 30. Theadministration system as claimed in claim 22, wherein the film dissolvescompletely in a period of less than 30 minutes in the mouth.
 31. Theadministration system as claimed in claim 22, wherein the film dissolvescompletely in a period of less than 15 minutes in the mouth.
 32. Theadministration system as claimed in claim 22, wherein a maximumconcentration of the active ingredient in the blood is reached in aperiod of less than 240 minutes after application.
 33. Theadministration system as claimed in claim 22, wherein a maximumconcentration of the active ingredient in the blood is reached in aperiod of less than 60 minutes after application.
 34. The administrationsystem as claimed in claim 22, wherein a maximum concentration of theactive ingredient in the blood is reached at a period of between 5 and30 min after application.
 35. The administration system as claimed inclaim 22, wherein the system additionally comprises at least oneexcipient selected from the group of flavorings, colorants, sweeteners,fillers, plasticizers, surface-active substances, solubilizers, liquidexcipient, pH stabilizers, disintegrants, solubility enhancers andabsorption enhancers.
 36. The administration system as claimed in claim22, wherein the active ingredient is present dissolved in the carriermaterial and/or a liquid excipient.
 37. The administration system asclaimed in claim 36, wherein the liquid excipient is a liquid lipophilicexcipient.
 38. The administration system as claimed in claim 22, whereinthe system contains a suspension comprising 40-50% by weight of theactive ingredient and 50-60% by weight of a polyalcohol and/or acellulose derivative as carrier material.
 39. The administration systemas claimed in claim 22, wherein the active ingredient is micronized. 40.The administration system as claimed in claim 22, wherein the systemcontains an amorphous presentation comprising 3-20% by weight of theactive ingredient and 80-97% by weight of a water soluble polymer ascarrier material.
 41. The administration system as claimed in claim 22,wherein the system contains an amorphous presentation comprising 5-10%by weight of the active ingredient and 90-95% by weight of a watersoluble polymer as carrier material, and the carrier material is asubstituted carbohydrate.
 42. The administration system as claimed inclaim 22, wherein the system has a monolayer or double-layerconstruction.
 43. A method of treatment for a disease comprisingadministering an administration system as claimed in claim 1 to apatient, wherein said disease is a mitochondrial disease, aneurodegenerative disease, a neuromuscular disease, a psychiatricdisorder, a metabolic disorder, cancer; multiple sclerosis or immunedysfunction.
 44. The method of treatment as claimed in claim 43, whereinsaid mitochondrial disease is selected from the group consisting ofLeber's hereditary optic neuropathy (LHON), autosomal dominant opticatrophy (DOA), macular degeneration, glaucoma, retinopathy, cataract,optic disc drusen (ODD), mitochondrial myopathy, encephalomyopathy,lactic acidosis, stroke-like symptoms (MELAS), myoclonic epilepsy withragged red fibers (MERRF), myoneurogenic gastrointestinalencephalomyopathy (MNGIE), Keamrns-Sayre syndrome, CoQ 10 deficiency,and mitochondrial complex deficiencies (1-5, CPEO); saidneurodegenerative disease is selected from the group consisting ofFriedreich's ataxia (FRDA), amyotrophic lateral sclerosis (ALS),Parkinson's disease, Alzheimer's disease, Huntington's disease,stroke/reperfusion injury, and dementia; said neuromuscular disease isselected from the group consisting of Duchenne muscular dystrophy (DMD),Becker muscular dystrophy (BMD), Limb-Girdle muscular dystrophy (LGMD),X-linked dilated cardiomyopathy (XLDCM), Pantothenate kinase-associatedneurodegeneration (PKAN), spinal muscular atrophy (SMA), multiplesclerosis, relapsing remitting multiple sclerosis (RR-MS), primaryprogressive multiple sclerosis (PP-MS), secondary progressive multiplesclerosis (SP-MS). Kugelberg-Welander disease, and Werdnig-Hottinanndisease; said psychiatric disorder is selected from the group consistingof schizophrenia, major depressive disorder, bipolar disorder, andepilepsy; said metabolic disorder is selected from the group consistingof ageing-related physical decline, obesity, overweight, type 11diabetes, and metabolic syndrome; and said immune dysfunction isselected from the group consisting of arthritis, psoriasis andrheumatoid arthritis.
 45. The method of treatment as claimed in claim43, wherein a dose of the administration system is an amount of equal toor less than 60 mg/kg/day.
 46. The method of treatment as claimed inclaim 43, wherein the pharmaceutical active ingredient of saidadministration system is idebenone and the idebenone is administered ina dosage ranging from 0.01 mg/kg/day to 10 mg/kg/day.
 47. The method oftreatment as claimed in claim 43, wherein the pharmaceutical activeingredient of said administration system is idebenone and theadministration system further comprises a polymer matrix wherein theidebenone is incorporated within the matrix as a suspension, asuspension after micronization, an emulsion, a micro- or nano-emulsion,or in solubilised form.
 48. The method of treatment as claimed in claim43, wherein said administering step comprises administering the activeingredient via the oral mucosa on or under the tongue in the buccalcavity or any other location in the oral cavity.
 49. The method oftreatment as claimed in claim 43, wherein said administration systemfurther comprises a second therapeutic agent.